Department of Orthopaedic Surgery
3471 Fifth Avenue
Pittsburgh, PA 15213
Phone: 412-605-3203
Fax: 412-687-0802
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Research
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| Department of Orthopaedic Surgery Research Mission Statement |
Stem Cell Research Laboratory (formerly Growth and Development Lab): |
| Orthopaedic Research Laboratory |
NeuroMuscular Research Laboratory |
| Orthopaedic Engineering and Sports Medicine Laboratory |
Orthopaedic BioDynamics Laboratory |
| Knee BioMechanics Laboratory |
Molecular Therapy Laboratory |
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| Department of Orthopaedic Surgery Research Mission Statement |
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The department has had another successful year in research and moved ahead on several fronts during this last year. Our research facilities have improved with the remodeling and extensive fit out of the Orthopaedic Research Laboratories in the Basic Science Tower of the University of Pittsburgh. This unit now houses the Ferguson Laboratory, Dr. James Kang and Dr. Gwen Sowa Co-Directors, the Mechanobiology Laboratory under Dr. James Wang, the Cartilage Restoration Laboratory under Dr. Constance Chu, and the Hand Laboratory under Dr. Zong-Ming Li, and the Molecular Therapeutics Laboratory, under the direction of Dr. Bing Wang. The new Knee Research Laboratory, under the direction of Dr. Christopher Harner, and the new Byodynamics Laboratory are under construction in the Rivertec Complex near the Sports Medicine Center on the Southside.
With the assistance of UPMC and the School of Medicine we have recruited Scott Tashman, PhD from the Henry Ford Hospital, Detroit, to build a new Orthopaedic Biodynamics Laboratory for computational evaluation of joint motion and function through the use of high speed cineradiography, which will allow in-vivo evaluations for knees, shoulders, spine, hips, and ankle and feet. Dr. Tashman brings an internationally recognized expertise in joint biomechanics using high-speed bi-planar radiography. Dr. Tashman’s work has been recognized by NIH research funding including a recent successful competitive renewal.
In addition to Dr. Tashman, Dr. Nam Vo has joined the department as a biologist working in the Ferguson Laboratory. Dr. Vo received his PhD from the University of California, Berkley and brings expertise in molecular and cell biology that he will apply to studies on disorders of the spine. Timothy Sell, PhD who has been a member of the Neuromuscular Research Laboratory under the direction of Dr. Scott Lephart, has received a joint appointment in our department to continue his work in kinematics. Finally, with the clinical appointment of Dr. Tony DiGioia, the department has benefited from a closer collaboration with the computational and surgical navigation research for which Dr. DiGioia has become internationally recognized. The addition of the new laboratories brings to 13 the number of defined and structured laboratories within department oversight.
With research ranging from molecular science to clinical outcomes and evidence-based medicine, the efforts of the faculty continue to focus on productivity and funding for their research. During this last year, 109 submissions for grant funding were filed from the department. As a result of similar efforts in the past years, this year brought an increase in total funding by 30%, and nearly a doubling since 2004. This level of funding places our program amongst the very top in federal funding in the nation. A significant boost in funding has come from the Department of Defense funding in separate awards to Drs. Huard, Lovell, and Lephart for studies on repairing muscle injuries or on preventing musculoskeletal injuries. Dr. Chu received her first R01 NIH award, and Dr. Johnny Huard received his first competitive renewal. With the downturn in the availability of federal funds for research in the coming year, the faculty will be challenged to find continued support for their research efforts.
The faculty has continued to support the Annual Meeting of the Orthopaedic Research Society. This year we had 55 posters or presentations at the meeting in Chicago, which represents a 20% increase over the previous year, and remarkably, 2.3% of the entire meeting’s proceedings. With the extensive efforts of the 17 members of the research faculty and 33 members of the clinical faculty, we have been increasingly successful in our research efforts, and with new recruitment of faculty we can expect even further success.
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| Stem Cell Research Laboratory (formerly Growth and Development Lab): |
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The SCRC is a fully collaborative center spanning many disciplines throughout the University of Pittsburgh Medical Center (UPMC) and the Children's Hospital of Pittsburgh. Many of the Center's collaborative colleagues reside in the focus groups within its laboratories.
The Departments of Orthopaedics, Cardiothroacic Surgery, and Rehabilitation along with the Pittsburgh Cancer Institute and the McGowan Center for Regenerative Medicine, among others, each share in the SCRC's goals for the future of cellular regenerative medicine
• Bone/Cartillage Inuries
• Cardiac Repair
• Endothelial/Vascular Cell
• Muscular Dystrophy Gene Therapy
• Muscle/Nerve Injuries
• Skeletal Muscle Repair
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| Contact Information | James Cummins
Senior Scientist
412.648.2641
jhc13@pitt.edu
Stem Cell Research Center
University of Pittsburgh
450 Technology Drive
2 Bridgeside Point, Suite 206
Pittsburgh, PA 15219 | | |
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Research at The Department of Orthopaedic Surgery
Stem Cell Research Lab
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| Orthopaedic Research Laboratory |
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A total of five laboratories: The Ferguson Laboratory for Orthopaedic and Spine Research, The Cartilage Restoration Laboratory, MechanoBiology Laboratory, Molecular Therapy Laboratory and The Hand Laboratory combine to form the Orthopaedic Research Laboratory—a state-of the art research facility benefiting from a unique multi-disciplinary approach to orthopaedic science. This diverse team of world renowned experts in molecular, mechanical, mechanobiology and regenerative research work collaboratively to take science from the benchtop and translate it into clinically relevant, life changing, solutions.
The Ferguson Laboratory for Orthopaedic and Spine Research
The Spine Research Laboratory, under the direction of James D. Kang, MD, is actively engaged in the development of novel cell and molecular biology based treatments of intervertebral disc degeneration.
Preclinical feasibility studies of gene therapy for the treatment of disc degeneration established that viral vectors were successful in delivering exogenous marker genes to rabbit lumbar intervertebral discs in-vivo [18]. Delivery of hTGF-beta growth factor genes to the rabbit disc resulted in increased synthesis of a critical extracellular matrix component, proteoglycan, which is crucial for disc hydration and healthy function [17]. More recently, the laboratory has developed a rabbit model of intervertebral disc degeneration, with quantitative outcome measures: x-ray, MRI, histology, and gene expression [5, 6]. Recent work [in press] has shown BMP-2 gene therapy results in preservation of MRI signal in this model.
While the above studies used adenoviral vectors to establish feasibility and efficacy of gene transfer for the treatment of intervertebral disc degeneration, the Spine Research Laboratory—with an eye towards clinical translation—has performed extensive safety studies [2], and has developed an adeno-associated viral vector strategy [4] which may be less immunogenic than the experimental adenovirus-based approaches (hence a better candidate for clinical translation.
Parallel studies have been performed in-vitro using intervertebral disc cells cultured from surgical specimens—demonstrating that human disc cells are responsive to gene transfer [15]. Additional in-vitro studies of cells from degenerated human discs has established that increased proteoglycan synthesis can be achieved by gene transfer of the catabolic inhibitor TIMP-1 [11]. Accordingly, the Spine Research Laboratory has established preliminary efficacy of pro-anabolic as well as anti-catabolic gene therapy strategies. The latter strategy presents theoretical advantages over the former such as less nutritional demand, and is supported by previous studies [19-21] showing that cells from degenerating discs produce elevated levels of catabolic agents that potentially could be blocked by an anti-catabolic gene transfer approach.
Throughout its history, the Spine Research Laboratory has taken a leading role in updating the general public and the scientific community on the exciting potential of molecular approaches to the treatment of spinal disorders [1, 3, 7-10, 12-14, 16].
Hand Research Laboratory
The Hand Research Laboratory is dedicated to the scientific study of the human hand. Our research team encompasses a wide spectrum of expertise including engineering, kinesiology, biomechanics, motor control,orthopaedics, occupational therapy, biology, and neurology. Our laboratory is equipped with cutting-edge engineering and clinical facilities for hand research. Our research has been mainly on the biomechanics and motor control of the human hand, with clinical applications to carpal tunnel syndrome.
Mechanobiology Lab
The MechanoBiology Laboratory is dedicated to pursue research in areas of fibroblast mechanobiology, soft tissue wound healing, functional tissue engineering, and biological applications of micro-fabrication and sensor technologies. The research team actively studies the cellular and molecular mechanisms of tendinopathy, a prevalent tendon disorder that affects millions of people in occupational and athletic settings. The research team also investigates the cellular and molecular mechanisms of scar tissue formation in injured tendons and ligaments and connective tissue responses to mechanical loading.
Cartilage Restoration Laboratory
The Cartilage Restoration Laboratory, headed by Dr. Constance Chu, has three research areas: Chondroprotection, Novel Cartilage Imaging Technologies, and Cartilage Tissue Engineering. Research representing each of these areas has been accepted for presentations at international meeting such as the Orthopaedic Research Society (ORS), and the American Orthopaedic Society for Sports Medicine (AOSSM) as well as several regional meetings. Dr. Chu was the recipient of the prestigious Kappa Delta Young Investigators Award at this year’s ORS/AAOS meeting. Please use this link to direct you to the AAOS article for further details on this award. http://www.aaos.org/News/acadnews/B4_2-14.asp
Chondroprotection
The main focus of Dr. Chu’s chondroprotection research is on optimizing survival of the stressed chondrocyte as a strategy to delay or prevent the onset of debilitating osteoarthritis. This work has been funded by a developmental grant from the National Institutes of Health to study oxidative stress on articular chondrocytes. Dr. Chu’s lab has continued to study metabolic changes induced in chondrocytes in hypoxic conditions and on reversal of metabolic deficient arthritic cartilage by inhibition of nitric oxide synthase.
The analytical imaging methods developed for our chondroprotection work are also being put to work in studies on cytotoxicity in articular chondrocytes induced by local anesthetics commonly used in arthroscopy, and of storage conditions used for osteochondral transplants by Dr. Chu, Dr. John Karpie, Nicole Papas and medical student Brian Dontchis. In the summer of 2006, our lab received the Best Poster award from AOSSM for the study on 0.5% bupivacaine cytotoxicity to chondrocytes. Dr. Karpie is continuing the exploration of other local anesthetic effects on chondrocytes in vitro as well as in small animal models. He has recently been invited to present the effects of lidocaine on bovine articular chondrocytes as a podium presentation at the 2007 annual American Orthopaedic Society for Sports Medicine (AOSSM) meeting.
Novel Cartilage Imaging Technologies
Optical coherence tomography (OCT) is a novel imaging technology with high potential for clinical applications in the area of early diagnosis of cartilage damage and for longitudinal assessment of cartilage repair and degeneration. Dr. Chu is the principal investigator for a new study, funded by an R01 research grant from the National Institutes of Health for the proposal: Enhanced Clinical Diagnosis of Early Osteoarthritis, which combines OCT with magnetic resonance imaging in the evaluation of patients after knee injury.
The search for treatments to prevent or delay the onset of osteoarthritis requires the ability to diagnose cartilage damage prior to the development of irreversible changes. As such, the use of novel imaging technology such as OCT complements efforts to develop chondroprotective treatments.
Cartilage Tissue Engineering
Dr. Chu is a charter member of the National Tissue Engineering Center (NTEC) headed by Dr. Alan Russell. Her proposal for “healing the Cartilage Injured Warfighter” contributed toward obtaining Department of Defense funding for the center. As a West Point graduate and former army officer, Dr. Chu has led her group in studying use of a novel biomimetic polymer to enable early return of the cartilage injured warfighter to combat. This polymer was developed by collaborator Dr. Kacey Marra of Bioengineering and Plastic Surgery. Unique aspects of this polymer include the ability to alter the release kinetics of growth factors. Continuing the efforts of Dr. Kaori Hayashi and Dr. Kenji Kobayashi, Dr. Mario Ferretti has further developed an in vivo rat osteochondral defect model for studying cartilage repair in the presence of polymer scaffolds and cell therapies. In collaboration with Dr. Xiao Xiao, Dr. Michael Pagnotto has been exploring the sustained expression of growth factors in human mesenchymal stromal cells used in tissue therapy of osteochondral defects. These ongoing studies will strive to determine the mechanisms for TGF-beta induced chondrogenesis of adult human bone marrow stem cells. The superb efforts of Lesa Lewis Werkmeister in cell culture and histology have been critical to the success of these studies.
We are grateful to Dr. Freddie Fu for his strong interest in and support of cartilage research. This year the Cartilage Restoration Laboratory has welcomed Dr. John Karpie and Dr. Michal Szczodry to our group. Dr. Karpie was a NIH Student Pre-Doctoral Intramural Research Training Fellow before attending medical school. Dr. Szczodry, a recent graduate of the Medical University of Warsaw, was involved in various orthopaedic research endeavors throughout medical school. Their prior research experience has greatly helped the ongoing efforts of the Cartilage Restoration Laboratory. Sadly, our lab has lost Dr. Mario Ferretti who recently returned to Brazil where he plans continue research as a clinician scientist.
Recent Publication from the Cartilage Restoration Laboratory:
• Chu CR*, Izzo NJ, Papas NE, Fu FH: Exposure to 0.5% Bupivacaine Is Cytotoxic To Bovine Articular Chondrocytes In Vitro. (Winner AOSSM Best Poster 2006) Arthroscopy 22(7): 693-9, 2006.
• Pagnotto MR, Wang Z, Karpie JC, Ferretti M, Xiao X, Chu CR: Adeno-associated Virus Gene Transfer of Transforming Growth Factor-β1 to Human Mesenchymal Stem Cells Improves Cartilage Repair. Gene Therapy (In press).
Cartilage Restoration Laboratory Personnel:
Constance R. Chu, M.D. Director
John Karpie, M.D. Research Resident
Michal Szczodry, M.D. Post-doctoral Research Fellow
Mario Ferretti, M.D. Post-doctoral Research Fellow
Lesa Lewis Werkmeister Research Specialist III
Nicole Papas Research Specialist I
MolecularTherapy Laboratory
The established molecular therapy laboratory, under the direction of Bing Wang MD., PhD., has interest focused on the virology of adeno-associated virus (AAV) and its utility as a novel gene therapy vector. In contrast to other viral vectors, recombinant adeno-associate virus (rAAV) is a promising gene replacement vector. It has demonstrated the best gene transfer efficiency and longevity among all viral and non-viral vectors tested in muscle tissue.In past years, Dr. Wang has been engaging in the projects of gene therapy for neuromuscular disorders, specifically Duchenne and Limb Girdle muscular dystrophies, using AAV viral vectors as gene vehicles. Deficiency of dystrophin protein causes Duchene muscular dystrophy (DMD), a most common disabling and lethal disease without treatment currently available. We first showed that AAV vectors carrying the human mini-dystrophin genes achieved efficient and stable correction of major biochemical and physiological defects of dystrophic muscle [1]. The further studies showed that AAV-mini-dystrophin gene treatment also improved mdx muscle contractile function [2]. Currently, the systemic human mini-dystrophin gene transfer by AAV vector intraperitoneal injection (i.p.) has been found to improve functions and life-span of dystrophin and utrophin double knockout (DKO) mice [3]. We discovered that the long-term expression of human mini-dystrophin and therapeutic benefits in transgenic mdx mice [4]. Importantly, the prolonged life-span was also observed in transgenic dystrophin/utrophin DKO mice. The large animal model is clinically and biologically superior to mdx model. We have first tested the biological functions of the AAV-mediated canine mini-dystrophin in the mdx mouse model [5]. The results indicated that the highly efficient canine mini-dystrophin was expressed in muscle tissue. Also, it could improve pathology and protect myofiber membrane integrity of dystrophic muscles. In a word, these experiments demonstrate that AAV mediated the human or canine mini-dystrophin ameliorates dystrophic muscle functions and life-span in rodent model. It provides the evidence of feasibility for DMD gene therapy. Beside Duchene muscular dystrophy, the research plan in long term of molecular therapy laboratory is involving in the gene therapy for the joint/tendon injury, muscle/nerve injures, skeletal muscle repair and age related bone lose/muscle atrophy. Currently, we cooperated with the other laboratories and made AAV constructs, such as AAV-sFLT1, AAV-BMP4, AAV-Decorin, AAV-MPRO, AAV-MMP1, AAV-IKBSR, AAV- cFLIP (University of Pittsburgh) and AAV-Osteoprotegerin (Wayne State University). Also, the lab is actively engaged in multi-applications of AAV vectors for gene therapy: 1)Therapeutic gene packaging in self-complimentary AAV vectors, 2) siRNA in AAV vectors, 3) Tet on/Tet off AAV vector, 4) Differrent serotype AAV vector purification and application. Base on the equipped facilities for AAV vector gene transfer studies and molecular biology, the molecular therapy laboratory is also a Vector Core for the projects involved in viral vectors development for gene therapy. The goal of this core is to construct vectors such as adeno-associated, adenoviral- and retoviral vectors for the projects. |
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| Contact Information | Lou Duerring
Research Administrator
412.648.1090
duerringml@upmc.edu
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Hand Laboratory
MechanoBiology Laboratory
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| NeuroMuscular Research Laboratory |
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Since 1990, The Neuromuscular Research Laboratory has initiated research in the area of proprioception and neuromuscular control, in an attempt to answer many of the clinical questions regarding the role of capsuloligamentous structures and the pathoetiology of joint injury. The objectives of our research are to study comprehensive profiles of an individual’s function by evaluating both the sensory and motor characteristics specific to several clinical conditions. Biomechanical and neuromuscular assessments under sport-simulated environments are used to determine specific variables including investigating the influence of weight distribution, muscle function, balance, flexibility, muscle memory, gender, aging and fatigue, as well as the effects of injury, surgery, and rehabilitation on joint stability. Deficiencies in body mechanics and muscle function are used to develop programs not only to improve performance but also minimize injury potential. Specific areas of research include the recognition and prevention of ACL injuries in female athletes, golf related injuries for golfers all skill levels, shoulder injuries in overhead athletes, and cycling injuries for elite and recreational cyclists.
http://www.pitt.edu/~neurolab
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| Contact Information | John Abt
Assistant Professor
412.432.3800
abtjp@upmc.edu
Neuromuscular Laboratory
3200 South Water Street
Pittsburgh PA 15203 | | |
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NeuroMuscular Research Laboratory
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| Orthopaedic Engineering and Sports Medicine Laboratory |
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Emerging Technology for the Reconstruction of the Torn Anterior Cruciate Ligament (ACL):
the Arthroscopic Double Bundle Technique.
Freddie H. Fu, M.D., D.Sc. (hon.), D.Ps. (hon.)
and Peter U. Brucker, M.D., M.Sc.
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| Contact Information | Lynne Welshons
Administrator
412.261.6523 X 254
welshons@pitt.edu
Department of Orthopaedic Surgery
UPMCenter for Sports Medicine
3200 South Water Street
Pittsburgh, PA 15203 | | |
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ACL Double Bundle
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| Orthopaedic BioDynamics Laboratory |
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| Contact Information | Diane L. Fajbik
Research Administrator
412.586.3960
dlf21@pitt.edu
Department of Orthopaedic Surgery
UPMC Center for Sports Medicine
3200 South Water Street
Pittsburgh, PA 15203 | | |
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| Knee BioMechanics Laboratory |
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The Knee Biomechanics Laboratory continues to maintain its commitment to research the causes and treatment of knee related injuries. Our staff consists of a diverse group of PhD’s, graduate students, orthopaedic residents, medical students, and undergraduates. While we are currently conducting our research in temporary lab spaces, our new laboratory is under the final stages of construction; we plan to be functional as early as February, 2007.
The new Biomechanics Laboratory will be housed in the recently constructed RiverTech Office Complex on South Water Street, a short distance from the UPMC Center for Sports Medicine. The facility is designed to facilitate collaboration between physicians, researchers, post docs, fellows, residents, graduate and undergraduate students. The lab features a comprehensive dissection lab and is equipped with the latest technology for in vitro biomechanics research. This technology includes material testing machines such as a biaxial, hydraulic Instron, robotic testing capabilities via universal force sensing Kuka, and Staubli robotic arms, and radiography of experimental specimens with a fluoroscopic C-arm. Further, the lab features 3D imaging technologies for in vivo tracking of knee kinematics.
While our new lab is in its final stages of formation, our staff has continued to pursue a variety of research interests. Recently, we have fully developed an experimental joint contact model in order to define the effects of clinically relevant meniscal tears in the medial compartment of the knee. We are currently developing a clinical correlation study in order to compare our in-vitro study evaluating meniscal tears to findings in the orthopaedic clinic. MRI’s and clinical evaluation data will be compared to the kinematic and contact area data we collected in the laboratory. We hypothesize that meniscal injury precipitates degenerative changes, the site of which will match regions of high pressure from the in-vitro study. This study is designed to be prospective in order to more carefully control the patient inclusion criteria and cater the MRI sequencing to our study.
Finally, our laboratory has set out to study patellofemoral instability. Our goal is to develop an in-vitro instability model that will study the anatomy and biomechanics of this common clinical problem. We will evaluate the contribution of the medial patellar
Contact Information
Lynne Welshons
Research Administrator
412 261-6532 X254
welshonslm@upmc.edu
Department of Orthopaedic Surgery
UPMC Center for Sports Medicine
3200 South Water Street
Pittsburgh, PA 15203
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| Molecular Therapy Laboratory |
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Bing Wang, MD, PhD
The newly established molecular therapy laboratory, under the direction of Bing Wang MD., PhD., has interest focused on the virology of adeno-associated virus (AAV) and its utility as a novel gene therapy vector. In contrast to other viral vectors, recombinant adeno-associate virus (rAAV) is a promising gene replacement vector. It has demonstrated the best gene transfer efficiency and longevity among all viral and non-viral vectors tested in muscle tissue.
In past years, Dr. Wang has been engaging in the projects of gene therapy for neuromuscular disorders, specifically Duchenne and Limb Girdle muscular dystrophies, using AAV viral vectors as gene vehicles. Deficiency of dystrophin protein causes Duchene muscular dystrophy (DMD), a most common disabling and lethal disease without treatment currently available. We first showed that AAV vectors carrying the human mini-dystrophin genes achieved efficient and stable correction of major biochemical and physiological defects of dystrophic muscle [1]. The further studies showed that AAV-mini-dystrophin gene treatment also improved mdx muscle contractile function [2]. Currently, the systemic human mini-dystrophin gene transfer by AAV vector intraperitoneal injection (i.p.) has been found to improve functions and life-span of dystrophin and utrophin double knockout (DKO) mice [3]. We discovered that the long-term expression of human mini-dystrophin and therapeutic benefits in transgenic mdx mice [4]. Importantly, the prolonged life-span was also observed in transgenic dystrophin/utrophin DKO mice. The large animal model is clinically and biologically superior to mdx model. We have first tested the biological functions of the AAV-mediated canine mini-dystrophin in the mdx mouse model [5]. The results indicated that the highly efficient canine mini-dystrophin was expressed in muscle tissue. Also, it could improve pathology and protect myofiber membrane integrity of dystrophic muscles. In a word, these experiments demonstrate that AAV mediated the human or canine mini-dystrophin ameliorates dystrophic muscle functions and life-span in rodent model. It provides the evidence of feasibility for DMD gene therapy.
Beside Duchene muscular dystrophy, the research plan in long term of molecular therapy laboratory is involving in the gene therapy for the joint/tendon injury, muscle/nerve injures, skeletal muscle repair and age related bone lose/muscle atrophy. Currently, we are cooperating with the other laboratories and making AAV constructs such as AAV-sFLT1, AAV-BMP4, AAV-Decorin, AAV-MPRO, AAV-MMP1, AAV-IKBSR, AAV- cFLIP (University of Pittsburgh) and AAV-Osteoprotegerin (Wayne State University).
Also, the lab is actively engaged in multi-applications of AAV vectors for gene therapy: 1).Therapeutic gene packaging in self-complimentary AAV vectors, 2). siRNA in AAV vectors, 3). Tet on/Tet off AAV vector, 4). Differrent serotype AAV vector purification and application. 5). AAV systemic gene delivery into skeletal muscle and cardiac muscles. Based on the equipped facilities for AAV vector gene transfer studies and molecular biology, the molecular therapy laboratory is also a Vector Core for the projects involved in viral vectors development for gene therapy. The goal of this core is to construct vectors such as adeno-associated-, adenoviral- and retoviral vectors for the orthopaedic gene therapy.
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